Isabella Tritto

Oxygen Radicals Can Induce Preconditioning in Rabbit Hearts

Indirect evidence suggests that oxygen radicals may contribute to ischemic preconditioning. We directly investigated whether exposure to oxygen radicals per se, in the absence of ischemia, could reproduce the beneficial effects of ischemic preconditioning on infarct size and on postischemic contractile dysfunction. In one branch of the study, isolated rabbit hearts underwent 30 minutes of total global ischemia and 45 minutes of reperfusion (n=6, control group). A second group, before ischemia/reperfusion, was exposed for 5 minutes to a low flux of oxygen radicals generated by purine/xanthine oxidase (P/XO), followed by a 15-minute washout (n=6). Oxygen radical pretreatment significantly improved postischemic recovery of contractile function. We then investigated in another branch of the study whether this preconditioning effect would also reduce infarct size and whether it was mediated by protein kinase C activation. Control hearts were subjected to coronary artery occlusion for 30 minutes, followed by 2.5 hours of reperfusion (n=6). A second group, before coronary occlusion, was exposed to oxygen radicals and washout as described (n=8). A third group was subjected to oxygen radical infusion, but an inhibitor of protein kinase C (polymyxin B, 50 micromol/L) was administered throughout subsequent ischemia (n=7). A fourth group was exposed to oxygen radicals in the presence of scavengers (superoxide dismutase, 250 U/mL; catalase 500, U/mL; n=8). Pretreatment with oxygen radicals markedly reduced infarct size, from 65+/-19% of risk region in controls to 12+/-4% (P<.05). Protein kinase C inhibition significantly attenuated this effect (infarct size, 37+/-9% of risk region; P<.05 versus P/XO; P=NS versus controls). Oxygen radical-induced preconditioning was prevented by scavengers (infarct size, 55+/-14% of risk region; P<.05 versus P/XO; P=NS versus P/XO+polymyxin B). Our data show that in the absence of ischemia, exposure to low concentrations of oxygen radicals can reproduce the beneficial effects of ischemic preconditioning on infarct size and postischemic recovery of left ventricular function. Thus, oxygen radicals might be potential contributors to ischemic preconditioning.

Patients With Acute Coronary Syndrome Show Oligoclonal T-Cell Recruitment Within Unstable Plaque Evidence for a Local, Intracoronary Immunologic Mechanism

Background— Recent studies indicate that T-cell activation may play an important role in the pathophysiology of acute coronary syndromes (ACS). However, although those studies detected T-cell expansion in peripheral blood cells, demonstration of specific T-cell expansion within the plaque of patients with ACS is lacking. The present study aims to address whether a specific, immune-driven T-lymphocyte recruitment occurs within the unstable plaque of patients with ACS. Methods and Results— We simultaneously examined the T-cell repertoire using CDR3 size analysis both in coronary plaques (obtained by directional atherectomy) and in peripheral blood of patients with either ACS (n=11) or chronic stable angina (n=10). Unstable plaques showed a 10-fold increase in T-cell content by quantitative PCR. Using spectratyping analysis, we found several specific T-cell clonotype expansions only in unstable plaque from each patient with ACS, indicating a specific, antigen-driven recruitment of T cells within unstable lesions. Conclusions— For the first time, T-cell repertoire was investigated directly into coronary plaques; using this approach, we demonstrate that coronary plaque instability in the setting of ACS is associated with immune-driven T-cell recruitment, specifically within the plaque.

A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings

Obstructive disease of the large coronary arteries is the prominent cause for angina pectoris. However, angina may also occur in the absence of significant coronary atherosclerosis or coronary artery spasm, especially in women. Myocardial ischaemia in these patients is often associated with abnormalities of the coronary microcirculation and may thus represent a manifestation of coronary microvascular disease (CMD). Elucidation of the role of the microvasculature in the genesis of myocardial ischaemia and cardiac damage-in the presence or absence of obstructive coronary atherosclerosis-will certainly result in more rational diagnostic and therapeutic interventions for patients with ischaemic heart disease. Specifically targeted research based on improved assessment modalities is needed to improve the diagnosis of CMD and to translate current molecular, cellular, and physiological knowledge into new therapeutic options.

The Role of Oxygen Free Radicals in Preconditioning

The preconditioning phenomenon was described for the first time in 1986 (Murry et al., 1986). In this classic article Murry and coworkers showed that the extent of necrosis following sustained ischemia could be largely reduced when the ischemic period was immediately preceded by four brief episodes of ischemia, only lasting 5 rain each. This phenomenon generated a very wide interest, since the degree of myocardial salvage that could be achieved in this seemingly paradoxical way was the highest ever seen in studies on myocardial protection. Since then, this phenomenon has been reproduced in several animal species (Li et al., 1990: Schott et al., 1990: Cohen et al., 1991: Liu et al., 1992), and a large number of studies has focused on preconditioning, trying to determine mechanisms of action. Among the various hypotheses that have been advanced (Table [) (Walker and Yellon, 1992: Lawson and Downey, 1993), some have not been confirmed by subsequent works, while others have gained substantial evidence. This review focuses on the possible role of oxygen free radicals in the pathogenesis of this phenomenon. This is an issue which has arisen very recently, and which has raised considerable interest and controversy. Oxygen free radicals are chemical species generated in little amounts during the normal metabolism of cells; due to their very reactive nature, they can oxidize many cellular components. Cells are normally equipped with endogenous scavenging systems; however, during reperfusion of post-ischemic tissues large amounts of oxygen free Table 1 Possible mediators of the preconditioning phenomenon

The Anti-anginal Drug Trimetazidine Reduces Neutrophil-mediated Cardiac Reperfusion Injury

Trimetazidine has no hemodynamic/antithrombotic actions. Hence, its anti-ischemic properties have been mostly attributed to its metabolic effects. However, this issue is not completely elucidated. We investigated whether inhibition of neutrophil activation may also contribute to its cardioprotective action. We first showed that trimetazidine inhibits neutrophil activation in vitro. We subsequently tested whether trimetazidine protects postischemic hearts from neutrophil-mediated injury. Four groups of rat hearts underwent 20 minutes of global ischemia: (1) controls, reperfused with neutrophil-enriched buffer for 5 minutes, followed by 40 minutes standard perfusate; (2) hearts from rats pretreated with trimetazidine for 1 week; (3) hearts in which 10−6 M trimetazidine was added to the perfusate, starting 5 minutes before ischemia and for the initial 15 minutes of reflow; (4) hearts from pretreated rats that also received trimetazidine in the perfusate. Postischemic impairment of contractile function was significantly attenuated by trimetazidine infusion (recovery of developed pressure: 68 ± 7% versus 42 ± 9% of baseline in controls; P < 0.05). Pretreatment alone was not effective, nor did it further improve the beneficial effects of infusion. Cardiac oxygen radical production at reflow (by electron paramagnetic resonance spectroscopy) was also reduced by trimetazidine, independently of direct scavenger effects. Thus, trimetazidine can protect postischemic hearts from neutrophil-mediated injury.

Methods to investigate coronary microvascular function in clinical practice.

A growing amount of data is increasingly showing the relevance of coronary microvascular dysfunction (CMVD) in several clinical contexts. This article reviews techniques and clinical investigations of the main noninvasive and invasive methods proposed to study coronary microcirculation and to identify CMVD in the presence of normal coronary arteries, also trying to provide indications for their application in clinical practice.

Spotlight on microcirculation: an update

Time for primary review 30 days. Over the past 3 decades there has been an increasing interest in the better understanding of the role of microcirculation under a variety of conditions. Therefore, in 1996 Cardiovascular Research devoted the whole October issue to microcirculation. Two years later the interest in this field is far from being reduced, as the number of articles published has remained high, with over 800 papers per year. The purpose of this article is to review several major studies which have appeared over the last 2 years in this field, which update the various key areas of research that were extensively reviewed in the 1996 issue. Oxygen delivery to tissue has long been considered to take place almost exclusively at the capillary level. However, it has progressively become appreciated that tissue oxygenation is the result of a complex process in which a substantial amount of oxygen is exchanged through arterioles, which in some tissues may be a greater oxygen source than capillaries (see review article by Intaglietta et al. [1]). Very recently, gas diffusion in postcapillary venules has also been supposed to occur, and it has been hypothesized that gas diffusive transfer may play an important role in regulating tissue oxygenation. Given the parallel arrangement of small arteries and veins in several tissues, oxygen transfer from arterial to venous vessels may result in diffusion shunting of oxygen, which may be detrimental to tissue oxygenation; on the other hand, diffusive transfer from arterioles to capillaries and among capillaries might contribute to homogeneous tissue oxygenation. Diffusion of CO2 might also improve tissue oxygenation, since CO2 diffusion from venules to arterioles would reduce pH in arterial blood and thus increase O2 release from hemoglobin. In this regard, it has recently been shown that in rat skeletal muscle … * Corresponding author. Tel.: +39-75-585-5842; fax: +39-75-585-5840

Impact of chronic antiplatelet therapy before hospitalization on ischemic and bleeding events in invasively managed patients with acute coronary syndromes: the ACUITY trial.

Aims: Presentation with an acute coronary syndrome (ACS) on chronic aspirin therapy is an independent predictor of adverse short-term outcomes. Whether this finding applies to chronic thienopyridine use, and with the contemporary invasive management of ACS, is unknown. Methods and results: In ACUITY, 13819 patients with moderate and high-risk ACS were studied; patients transferred from an outside hospital were excluded from the present analysis, given uncertain preadmission antiplatelet status. Endpoints included major adverse cardiovascular events (MACE: death, myocardial infarction, or unplanned revascularization), major bleeding, and net adverse clinical events (NACE). Among 11313 study patients, 31 % were naive for antiplatelet agent, 49% were receiving aspirin alone, and 20% were on dual antiplatelet therapy. Chronic antiplatelet users were older and had a higher risk profile. After adjusting for baseline differences, chronic antiplatelet therapy (single or dual) was not associated with an increased incidence of 30-day MACE, bleeding, or NACE. However, patients on chronic aspirin or dual antiplatelet therapy at presentation had significantly higher 1-year rates of MACE [odds ratio (95% confidence interval) = 1.17 (1.01–1.36), P = 0.03 and 1.29 (1.02–1.64), P = 0.03, respectively]. Patients presenting on dual antiplatelet therapy had significantly greater adjusted MACE at 1-year than those on aspirin alone [odds ratio (95% confidence interval) = 1.34 (1.15–1.56), P < 0.0001]. Conclusion: Contrary to earlier studies, prior antiplatelet therapy was not associated with an increased risk of adverse outcomes at 30 days in invasively managed patients. Such use did, however, independently predict 1-year ischemic MACE, with outcomes worse for patients presenting on chronic dual antiplatelet therapy compared with aspirin alone.

Association of beta-blocker treatment with mortality following myocardial infarction in patients with chronic obstructive pulmonary disease and heart failure or left ventricular dysfunction: a propensity matched-cohort analysis from the High-Risk Myocardial Infarction Database Initiative

To determine the influence of baseline beta‐blocker use on long‐term prognosis of myocardial infarction (MI) survivors complicated with heart failure (HF) or with left ventricular dysfunction and with history of chronic obstructive pulmonary disease (COPD).

Mepindolol reduces myocardial necrosis in rats with coronary artery occlusion.

Summary: Mepindolol is a newly developed β-adrenergic blocking agent reported to counteract the chronotropic effect of catecholamines, with only little effect on contractility. This study was designed to assess whether or not mepindolol is effective in reducing infarct size. Accordingly, 16 rats, serving as controls, underwent coronary artery occlusion and did not receive any treatment; an additional 19 were treated with mepindolol (1 mg/kg s.c. t.i.d.) for 48 h. Finally, a third group (n = 18) underwent sham operation. Forty-eight hours later, infarct size was calculated from left ventricular creatine phosphokinase activity and found to average 52.4 ± 7.8% (mean ± SEM) of the left ventricle in control rats and 35.6 ± 5.4% in treated rats (p < 0.05). Left ventricular phospholipid content averaged 0.79 ± 0.08 μg P/mg protein in sham-operated rats and 0.61 ± 0.04 μg P/mg protein in control animals. In contrast, in mepindolol-treated rats, phospholipid concentration was 0.70 ± 0.04 μg P/mg protein (p < 0.05), this suggesting a protective effect of the drug on ischemia-induced phospholipid degradation. The long-term effect of mepindolol on left ventricular hydroxyproline concentration was assessed 21 days post–coronary occlusion. Infarct size calculated by this method was 30.2 ± 4.8% of left ventricle in 21 control animals and 18.2 ± 4.2% in 28 treated rats (p < 0.05), indicating that, as for the acute necrosis, the extent of scar development after coronary artery occlusion can be reduced by mepindolol.